Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia.
BACKGROUND
Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1) gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy) mouse, which has a deletion in the Dtnbp1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study.


RESULTS
In a rotarod test, sdy mice did not exhibit motor learning whilst the wild type mice did. In a Barnes circular maze test both sdy mice and wild type mice learned to selectively locate the escape hole during the course of the training period and in the probe trial conducted 24 hours after last training. However, sdy mice did not locate the correct hole in the retention probe tests 7 days after the last training trial, whereas wild type mice did, indicating impaired long-term memory retention. A T-maze forced alternation task, a task of working memory, revealed no effect of training in sdy mice despite the obvious effect of training in wild type mice, suggesting a working memory deficit.


CONCLUSIONS
Sdy mouse showed impaired long-term memory retention and working memory. Since genetic variation in DTNBP1 is associated with both schizophrenia and memory function, and memory function is compromised in patients with schizophrenia, the sdy mouse may represent a useful animal model to investigate the mechanisms of memory dysfunction in the disorder.
Takao
Keizo
K
Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan. keizo@fujita-hu.ac.jp
Toyama
Keiko
K
Nakanishi
Kazuo
K
Hattori
Satoko
S
Takamura
Hironori
H
Takeda
Masatoshi
M
Miyakawa
Tsuyoshi
T
Hashimoto
Ryota
R
D000818:Animals; D001007:Anxiety / Q000150:complications / Q000503:physiopathology; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000150:complications / Q000503:physiopathology*; D057567:Memory, Long-Term / Q000502:physiology*; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000502:physiology; D012153:Retention, Psychology / Q000502:physiology*; D012559:Schizophrenia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D013647:Task Performance and Analysis
D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins